Effect of external therapies of traditional Chinese medicine on constipation in patients with CRF: A meta-analysis

Objective The purpose of this study was to evaluate the curative effect of external therapies of traditional Chinese medicine on constipation in patients with chronic renal failure and to provide scientific theoretical basis for clinical practice. Method We searched the English database of PubMed, EMBASE, the Cochrane Library and the Web of Science and Chinese database of CNKI, Wan fang database, VIP Database and China Biomedical Literature Database up to December 2022. Randomized controlled trials (RCTs) involving constipation in patients with CRF that compared external therapies of traditional Chinese medicine and routine treatment to routine treatment were eligible for the analysis. A meta-analysis of the outcome indicators including total efficiency, weekly defecation times, defecation time, defecation difficulty score, patient-assessment of constipation quality of life and adverse events of treatment were performed. The analysis was performed by using Review Manager version 5.3. Result A total of 23 studies were included, with 1764 patients. Meta-analysis results showed that compared with the control group, the test group could significantly increase weekly defecation times(MD = 0.94, 95%CI(0.70, 1.18), Z = 7.74, P < 0.00001), reduce defecation time(MD = -2.92, 95%CI(-3.69, -2.16), Z = 7.49, P < 0.00001), reduce defecation difficulty score(MD = -1.92, 95%CI(-2.45, -1.39), Z = 7.11, P < 0.00001), improve the quality of life in patients with constipation(MD = -7.57, 95%CI(-10.23, -4.91), Z = 5.58, P < 0.00001) and obtain a higher total effective rate of treatment(OR = 4.53, 95%CI(3.27, 6.29), Z = 9.07, P < 0.00001). In terms of safety, there was no statistical significance in the incidence of adverse events between two groups(OR = 0.35, 95%CI(0.04, 2.95), Z = 0.96, P = 0.34). Conclusion The combination of external therapies of traditional Chinese medicine and routine treatment could achieve an excellent curative effect, and there was no specific adverse event. However because of the limited level of current evidence, more high-quality trials are needed in the future.5


Introduction
Constipation is a common disease, It is reported that constipation is a symptom that affects 11-20% adult population every year [1] .And the mean prevalence rate of chronic constipation is approximately 14% all over the world [2] .In China the prevalence rate in adults is 7.0%~20.3% [3].From the most recently published diagnosis criteria which is from Rome Committee in 2016 (Rome IV), The definition of constipation includes that straining, lumpy or hard stools, the sensation of incomplete evacuation, the sensation of anorectal obstruction or blockage, the use of manual manoeuvres to facilitate defecation, and fewer than three bowel movements per week, any two or more items of these symptoms continued for at least 3 months in the preceding 6 months can qualify the patient for a diagnosis of functional constipation [4] .
Constipation may occur because of a primary motor disorder involving the colon or can be induced by kinds of secondary causes, It may be associated with a large number of diseases or as an adverse effect of many drugs [5] .For example, uremia in CKD (chronic kidney disease) patients, electrolyte disorders like hypercalcemia, hypokalemia (severe) and hypothyroidism (severe) which are common symptoms in uremia are some of important causes of constipation [5] .And constipation is also a more common problem for patients receiving hemodialysis [6] .According to statistics, approximately 53% patients with end-stage renal disease who are receiving dialysis are suffering from constipation [7] .And the incidence of constipation is 71.7% in haemodialysis patients and 14.2% in peritoneal dialysis patients respectively [8] .A global multicenter study showed that chronic constipation could significantly reduce the quality of life, as well as in China [9][10] .The treatment of constipation includes general treatment of reasonable diet, plenty of water, moderate exercise and establishing good defecation habits, which are the basic treatment measures for patients with chronic constipation, and medical treatment includes the administration of stimulant and osmotic laxatives, new intestinal secretagogues and peripherally restricted μ-opiate receptor antagonists et al [5,11] .Abusing of laxatives or repeated medical treatment can bring patients a heavy financial burden [12] .For the past few years, external therapies of traditional Chinese medicine had played a very important cause role in the treatment for constipation in people diagnosed with chronic renal failure [13] .
However, whether traditional Chinese external therapies are effective or superior to routine treatment measures remain to be clarified.
In order to further evaluate the curative effect of external therapies of traditional Chinese medicine in chronic constipation and to provide scientific theoretical basis for clinical practice, this study systematically evaluated and analyzed the clinical research literature of external therapies of traditional Chinese medicine on constipation in patients with chronic renal failure.This meta-analysis was performed in accordance with the recommendations of the Cochrane handbook for systematic reviews of interventions and was reported in compliance with Meta-Analyses (PRISMA) statement guidelines.

Data sources and search strategy
We conducted a search of English database of PubMed, EMBASE, the Cochrane

Inclusion and exclusion criteria
The inclusion criteria were developed by using a PICOS (Patient, Intervention, Comparators, Outcome, Study design) approach.The study subjects were adult patients who were diagnosed with CRF and constipation and there were specific diagnostic criteria for constipation in the study; the study compared routine treatment combined with different ways of external therapies of traditional Chinese medicine versus routine treatment and there was no limit to the course of treatment; all the studies were randomized controlled trials.The outcome indicators included total effective rate, weekly defecation times, defecation time, clinical constipation scores, PAC-QOL and occurrence of adverse events.
Studies were rejected according to the exclusion criteria as follows: constipation was caused by organic lesions of the intestinal tract(such as tumor, Crohn's disease, colonic polyp, intestinal tuberculosis et al), repeatedly published literature or data repeated in other articles or data included in other articles, no clear evaluation standard of curative effect, no data available for this study in the article, animal experiments, reviews, case reports, expert experience reports, conference abstracts and article not in Chinese or English.

Data extraction
Data from the retrieved literature were extracted and analyzed independently by two reviewers (WY and YYS), if there were different opinions about the quality of a study, a third reviewer examined the controversial literature and discussed it with the two aforementioned reviewers to resolve the discussion.And data were included only if the three reviewers achieved consensus regarding the data.The extracted data mainly included the first author, publication year, sample size, age, sex, intervention, treatment time, outcome indications and so on.

Quality assessment
Two authors (WY and YYS) independently evaluated risk of methodological quality of the included literature by using the Cochrane risk-of-bias tool.There were seven items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias.The evaluation results of each item were divided into three levels: low-risk, unclear and high-risk, which were represented by a score of bias.

Statistical analyses
Analyses were performed using Review Manager 5.3.Dichotomous outcome data were measured with odds ratio (OR) and 95% CI, and continuous outcomes were measured with mean difference (MD) or standardized mean difference (SMD) and 95% CI, and we assessed changes based on mean values and standard deviations (SDs) changes between the pre-treatment and post-treatment.The heterogeneity between studies was evaluated by the chi-square-based Q statistical test using the heterogeneity χ 2 and I 2 statistics.In all analyses, P < 0.05 was deemed to represent significant heterogeneity, and the random-effects models were used for the meta-analysis of each indicator and vice versa.In addition, publication bias was assessed by using funnel plots.

Searching Results
The search strategy generated 1409 citations, of which 79 published articles appeared to be relevant to the systematic review and were retrieved for further assessment.Of these studies, 56 were excluded.Overall we included 23 eligible articles reporting on 23 separate trials ultimately.These trails contained 1764 patients who were allocated to test group and control group.The search process was illustrated in Fig. 1, and detailed characteristics of the eligible studies were listed in Table 1.d Table 1 Characteristics of trails included in the study.
medicine clinical diagnosis and efficacy [30] ".The effectivity means that the patient can defecate once within 3 days, and the clinical symptoms are relieved, the invalidation of treatment means that constipation symptoms do not improve or increase.Total effective rate = (number of effective cases/total cases) × 100%.
There was no statistical heterogeneity among the studies (I 2 = 0%, P = 0.87), the fixed effect model was used for analysis.The results showed that there did have significantly statistical differences in total efficiency between treatment and control group〔OR=4.53，95%CI(3.27，6.29)，Z=9.07，P < 0.00001;Fig 3〕.
Fig. 3 Forest plot of total efficiency in the treatment group and the control group.

3.3.2
Weekly defecation times.7 studies [14,17,22,27,29,31,34] evaluated the weekly defecation times after the treatment of which 266 patients were assigned to treatment group and 265 patients were assigned to control group respectively.There had statistical heterogeneity among the studies (I 2 = 72%, P = 0.002), the random effect efficacy?failure?
meaning not clear efficacy or efficiency?    [14,17,22,23,31,34] uated the defecation time after the treatment of which 216 patients were assigned to treatment group and 215 patients were assigned to control group respectively.There had no statistical heterogeneity among the studies (I 2 = 0%, P = 0.73), the fixed effect model was used for analysis.
The results showed that there did have significantly statistical differences in defecation time changes between baseline and end of treatment between treatment and control group〔MD = -2.92，95%CI(-3.69，-2.16)，Z=7.49，P < 0.00001 Fig5〕.3 studies [19,24,28] compared the defecation difficulty score after the treatment of which 115 patients were assigned to treatment group and control group respectively.There had statistical heterogeneity among the studies (I 2 = 63%, P = 0.07), the random effect model was used for analysis.The results showed that there did have significantly statistical differences in defecation difficulty score changes between baseline and end of treatment between treatment and control group

3.3.5
Patient-Assessment of Constipation Quality Of Life (PAC-QOL).5 studies [29,30,33,34,36] compared the quality of life in patient with constipation after the treatment of which 247 patients were assigned to treatment group and 246 patients were assigned to control group respectively.There had statistical heterogeneity among the studies (I 2 = 64%, P = 0.03), the random effect model was used for analysis.The results showed that there did have significantly statistical differences in quality of life in patients between baseline and end of treatment between treatment and control group〔MD =

3.3.6
Adverse events of treatment.3 studies [21,32,35] reported the occurrence of adverse events during treatment, including intestinal obstruction, hematochezia and allergic reactions characterized by skin redness and itching after auricular point sticking.
There had statistical heterogeneity among the studies (I 2 = 55%, P = 0.11), the random effect model was used for analysis.The results showed that there had no significantly statistical differences in the incidence of adverse events between treatment and control group〔OR=0.36，95%CI(0.04，2.95)，Z=0.95，P =0.34; Fig

8〕.
Fig. 8 Forest plot of adverse events in the treatment group and the control group.

Funnel Plot of Publication Bias
As shown in Figure 9, a funnel chart analysis of clinical effectiveness rate was performed.Results showed that the scatter is basically distributed at the top of the funnel chart which indicated the risk of publication bias in the clinical efficacy of constipation is low.
was was that Fig. 9 Funnel plot of effectiveness rate in the treatment group and the control group.

Discussion
Constipation is a prevalent disorder with a global prevalence of 14% [2] .It's prevalence increases with age and is almost twice as common in women than men [37] , which can significantly interfere with patients' daily living and well-being and consumes resources in healthcare systems worldwide [38][39][40] .The prevalence of constipation in dialysis patients is reported to be 36.3%~66.7% [41]and has been shown to be higher in patients with CKD than the general population, particularly among those undergoing dialysis [42,43] .Water restriction, water removal by dialysis, inadequate intake of dietary fiber due to potassium restriction and the associated changes in intestinal microflora, lack of exercise, diabetic autonomic nervous system disorder, intake of potassium inhibitors and phosphorus adsorbents may be the reasons why dialysis patients are prone to develop constipation [44,45] .However, A considerable proportion of constipated people were reported dissatisfied with conventional treatments, because of the lack of life style sense of effectiveness and the side effects [46][47][48][49] .
In recent years, several studies had shown that external therapies of traditional Chinese medicine such as acupuncture, moxibustion, massage, cupping therapy and ear acupunctures and so on were effective in the treatment of constipation, and compared with conventional treatments, they were more effective, non-toxic and side effects, low cost, more convenient operation and suitable for long-term medication [50][51][52][53][54] .And in this meta-analysis, the therapeutic effect of external therapy of traditional Chinese medicine on chronic renal failure patients with constipation was explored.Our results suggested that external therapy of traditional Chinese medicine can significantly increase the frequency of weekly defecation, shorten the defecation time, and obtain a higher total effective rate of treatment.And there were no obvious adverse events in the course of treatment.
A meta-analysis [55] in 2022 showed that treatment with Seed-embedding at otopoints plus routine treatment had an better effect on dialysis patients with constipation compared to treatment with routine treatment alone.However, that study only discussed the external therapy of traditional Chinese medicine, which was based on Seed-embedding at otopoints and that study only included patients with maintenance hemodialysis.Our meta-analysis covers a wider range of subjects and treatments.
The meta-analysis had some limitations.First, Some studies did not describe the randomization process or the procedure of allocation concealment in detail; Second, the sample size was small in some studies.Third, most of the studies in this meta-analysis were Chinese-based, which may have caused regional, language, and , without Enter a financial disclosure statement that describes the sources of funding for the work included in this submission.Review the submission guidelines for detailed requirements.View published research articles from PLOS ONE for specific examples.This statement is required for submission and will appear in the published article if the submission is accepted.Please make sure it is accurate.Unfunded studies Enter: The author(s) received no specific funding for this work.Funded studies Enter a statement with the following details: Initials of the authors who received each award • Grant numbers awarded to each author • The full name of each funder • URL of each funder website • Did the sponsors or funders play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript?• NO -Include this sentence at the end of your statement: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.• YES -Specify the role(s) played.• * typeset Competing Interests Use the instructions below to enter a competing interest statement for this submission.On behalf of all authors, disclose any competing interests that could be perceived to bias this work-acknowledging all financial support and any other relevant financial or nonfinancial competing interests.This statement is required for submission and will appear in the published article if The authors have declared that no competing interests exist.Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation the submission is accepted.Please make sure it is accurate and that any funding sources listed in your Funding Information later in the submission form are also declared in your Financial Disclosure statement.View published research articles from PLOS ONE for specific examples.NO authors have competing interests Enter: The authors have declared that no competing interests exist.Authors with competing interests Enter competing interest details beginning with this statement: I have read the journal's policy and the authors of this manuscript have the following competing interests: [insert competing interests here] /A" if the submission does not require an ethics statement.General guidance is provided below.Consult the submission guidelines for detailed instructions.Make sure that all information entered here is included in the Methods section of the manuscript.N/A Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Format for specific study types Human Subject Research (involving human participants and/or tissue) Give the name of the institutional review board or ethics committee that approved the study • Include the approval number and/or a statement indicating approval of this research • Indicate the form of consent obtained (written/oral) or the reason that consent was not obtained (e.g. the data were analyzed anonymously) • Animal Research (involving vertebrate animals, embryos or tissues) Provide the name of the Institutional Animal Care and Use Committee (IACUC) or other relevant ethics board that reviewed the study protocol, and indicate whether they approved this research or granted a formal waiver of ethical approval • Include an approval number if one was obtained • If the study involved non-human primates, add additional details about animal welfare and steps taken to ameliorate suffering • If anesthesia, euthanasia, or any kind of animal sacrifice is part of the study, include briefly which substances and/or methods were applied • Field Research Include the following details if this study involves the collection of plant, animal, or other materials from a natural setting: Field permit number • Name of the institution or relevant body that granted permission • Data Availability Authors are required to make all data underlying the findings described fully available, without restriction, and from the time of publication.PLOS allows rare exceptions to address legal and ethical concerns.See the PLOS Data Policy and FAQ for detailed information.
Library and the Web of Science and Chinese database of China National Knowledge Infrastructure (CNKI), Wan-Fang database, VIP Database and China Biomedical Literature Database (CBM) which were published between establishment of the database and December 2022 using the search terms constipation, Renal Insufficiency, Chronic, Renal Dialysis, Acupuncture Therapy, Moxibustion, Acupoint sticking therapy, Tuina, Massage, Cupping Therapy, Auricular point sticking, Acupuncture, Ear, Enema, Acupoint Catgut-Embedding Therapy, placebo and RCTs.

Figure 1
Figure 1 Flow diagram of literature search and selection of included

Fig. 2 1
Fig. 2 Risk of bias graph of included studies

was
model was used for analysis.The results showed that there did have significantly statistical differences in weekly defecation times changes between baseline and end of treatment between treatment and control group〔MD = 0.94，95%CI(0.70，1.18)，Z=7.74，P < 0.00001;Fig 4〕.

Fig. 4
Fig. 4 Forest plot of weekly defecation times changes between baseline and end of

Fig. 5
Fig. 5 Forest plot of defecation time changes between baseline and end of treatment in

Fig. 6
Fig. 6 Forest plot of defecation difficulty score changes between baseline and end of

Fig. 7
Fig. 7 Forest plot of PAC-QOL changes between baseline and end of treatment in the Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Quality of trialsOf the 23 eligible randomized controlled trials, 18 studies described the grouping method as the random number table method, 4 studies only mentioned "random" and 1 study was numbered according to the order of hospital admission and then grouped according to the random number table method.And only 2 studies were double blinded trials.None of the studies reported the reporting bias and the existence of other biases(Fig2).